Naphthoquinones, pro-drugs, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10829427-B2
Application number	US-201616063347-A
Country	US
Kind code	B2
Filing date	Dec 16, 2016
Priority date	Dec 18, 2015
Publication date	Nov 10, 2020
Grant date	Nov 10, 2020

Abstract

Provided herein are naphthoquinones compounds such as those with a hydrogen bond donating group of the formula (I): wherein: R 1 , R 2 , R 3 , R 4 , R 5 , and n are as defined herein. Also provided herein are pharmaceutical composition of the present compounds and methods of treatment using the compounds including their use in the treatment of cancer.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
R 1 is halo, nitro, substituted alkyl (C≤8) , substituted alkoxy (C≤8) , or —NR a R b , wherein:
R a or R b are each independently hydrogen or —C(O)-alkoxy (C≤12) , alkyl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups; or
when n is more than 1, then both R 1 are taken together and are an alkoxydiyl (C≤6) or substituted alkoxydiyl (C≤6) ; or
—O-alkanediyl (C≤6) -R c , wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;

R 2 is absent or alkyl (C≤12) , cycloalkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;

provided that R 2 is absent when the atom to which R 2 is bound is a part of a double bond, and when the atom to which R 2 is bound is part of a double bond, then R 2 is absent;
R 3 is absent or alkyl (C≤12) , cycloalkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , —(CH 2 CH 2 O) m R d , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;
R d is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
m is 1, 2, 3, 4, or 5;

provided that R 3 is absent when the atom to which R 3 is bound is a part of a double bond, and when the atom to which R 3 is bound is part of a double bond, then R 3 is absent;
R 4 is hydrogen, halo, alkyl (C≤6) , or substituted alkyl (C≤6) ;
R 5 is absent or alkyl (C≤12) , acyl (C≤12) , or a substituted version of either of these groups;
provided that R 5 is absent when the atom to which R 5 is bound is a part of a double bond, and when the atom to which R 5 is bound is part of a double bond, then R 5 is absent; and
n is 1, 2, 3, or 4;
provided that when R 2 and R 5 are acyl (C≤12) or substituted acyl (C≤12) , then R 3 is alkyl (C≤12) or substituted alkyl (C≤12) ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 further defined as:

wherein:
R 1 is halo, nitro, substituted alkyl (C≤8) , substituted alkoxy (C≤8) , or —NR a R b , wherein:
R a or R b are each independently hydrogen or —C(O)-alkoxy (C≤12) , alkyl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups; or
when n is more than 1, then both R 1 are taken together and are an alkoxydiyl (C≤6) or substituted alkoxydiyl (C≤6) ; or
—O-alkanediyl (C≤6) -R c , wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;

R 2 is absent or alkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;

provided that R 2 is absent when the atom to which R 2 is bound is a part of a double bond, and when the atom to which R 2 is bound is part of a double bond, then R 2 is absent;
R 3 is absent or alkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , —(CH 2 CH 2 O) m R d , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;
R d is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
m is 1, 2, 3, 4, or 5;

provided that R 3 is absent when the atom to which R 3 is bound is a part of a double bond, and when the atom to which R 3 is bound is part of a double bond, then R 3 is absent;
R 4 is hydrogen, halo, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
n is 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , further defined as:

wherein:
R 1 is halo, nitro, substituted alkyl (C≤8) , substituted alkoxy (C≤8) , or —NR a R b , wherein:
R a or R b are each independently hydrogen or —C(O)-alkoxy (C≤12) , alkyl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups; or
when n is more than 1, then both R 1 are taken together and are an alkoxydiyl (C≤6) or substituted alkoxydiyl (C≤6) ; or
—O-alkanediyl (C≤6) -R c , wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;

R 3 is alkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , —(CH 2 CH 2 O) m R d , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;
R d is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
m is 1, 2, 3, 4, or 5;

R 4 is hydrogen, halo, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
n is 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 further defined as:

wherein:
R 1 is halo, nitro, substituted alkyl (C≤8) , substituted alkoxy (C≤8) , or —NR a R b , wherein:
R a or R b are each independently hydrogen or —C(O)-alkoxy (C≤12) , alkyl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups;

R 3 is alkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , —(CH 2 CH 2 O) m R d , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;
R d is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
m is 1, 2, 3, 4, or 5; and

R 4 is hydrogen, halo, alkyl (C≤6) , or substituted alkyl (C≤6) ;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 further defined as:

wherein:
R 1 is halo, nitro, substituted alkyl (C≤8) , substituted alkoxy (C≤8) , or —NR a R b , wherein:
R a or R b are each independently hydrogen or —C(O)-alkoxy (C≤12) , alkyl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups; and

R 3 is alkyl (C≤12) , acyl (C≤12) , -alkanediyl (C≤6) -R c , —(CH 2 CH 2 O) m R d , or a substituted version of any of these groups; wherein:
R c is amino, alkylamino (C≤8) , dialkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups;
R d is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and
m is 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 1 is —NR a R b , wherein:
R a or R b are each independently hydrogen or —C(O)-alkoxy (C≤12) , alkyl (C≤12) , acyl (C≤12) , alkylsulfonyl (C≤12) , arylsulfonyl (C≤12) , or a substituted version of any of these groups.

7. The compound of claim 6 , wherein R a is acyl (C≤8) or substituted acyl (C≤8) .

8. The compound o

Assignees

• Univ Texas

Inventors

• Gao Jinming
• Liu Yuliang
• Wei Qi
• Ma Xinpeng
• Huang Gang

Classifications

• C07C205/46

  the carbon skeleton containing carbon atoms of quinone rings · CPC title

• C07C271/30

  to a carbon atom of a six-membered aromatic ring being part of a condensed ring system · CPC title

• C07D317/70

  condensed with ring systems containing two or more relevant rings · CPC title

• C07C233/31

  with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom · CPC title

• C07C311/09

  the carbon skeleton being further substituted by at least two halogen atoms · CPC title